Our studies of age-associated changes in brain neurochemistry have demonstrated the following changes. (1) An increase in cerebellar DNA occurs with aging that can be correlated with a small increase in thymidine kinase activity. (2) The thymidine kinase present in the aging cerebellum was inhibited by deoxycytidine trephosphate in contrast to the new born enzyme. (3) The "old" thymidine kinase showed a 5-fold higher Km than the "young" enzyme. (4) Polyacrylamide gel electrophoresis revealed the presence of different molecular forms of thymidine kinase during development and aging. The aged cerebellum appears to be characterized by the presence of a kinetically inefficient, rapidly migrating form of thymidine kinase. (5) Analysis of cholinerage synaptic competence demonstrated a 59 percent decrease in specific activity of choline acetylase in mouse cerebella from 12-21 months of age. This reduction in choline acetylase activity is not seen in the telencephalon or in the brain stem and is restricted to the cerebellum. Experiments are planned to examine the proliferation of glial cells and the possible deterioration of the cellular environment in the aging mouse cerebellum. We also plan to determine molecular alterations and genetic regulation of mitochondrial glycerol-3-phosphate oxidase enzyme complex in rat brain, with the expectation that this study will provide valuable information regarding the control of genomic expression in aging tissue.